Clinical use of cardiac glycosides is complicated by the high incidence of cardiotoxicity, manifested by potentially life-threatening arrhythmias. Experimental evidence in animals suggests an important facilitatory role for the autonomic nervous system in digitalis-induced arrhythmias. In prior studies, we have attempted to dissociate the neurotoxic properties of digitalis from the direct inotropic effects by utilizing charged digitalis derivatives that fail to cross the blood brain barrier and thus fail to enter the central nervous system. However, these compounds are as arrhythmogenic as those with more ready access to the central nervous system, and neural ablation provides protection against the toxic effects of these compounds. These studies, together with preliminary neural ablation data, suggest that digitalis activates areas in the brainstem within 2 mm of the abex that are devoid of effective blood brain barrier. A region meeting this description is the area postremia, known to be the emetic center for digitalis. The studies outlined in this application propose to localize the region or regions in the brainstem involved in digitalis activity stimulation. The proposal also deals with studies on selective agents that may act on this arrhythmia facilitatory center selectively decreasing the arrhythemogenic action of digitalis while not effecting the inotropic effects. Experimental evidence suggests that ventricular arrhythmia due to digitalis may originate in Purkinje fibers. This proposal outlines experiments to study if Purkinje fibers are more sensitive than "working" myocardium to the toxic effects of digitalis. Also the influence of the nervous system will be studied as it might affect the sensitivity of the Purkinje fibers to toxic doses of digitalis in vivo. Thus further characterization of the mechanism underlying digitalis toxicity and the role the central nervous system plays in this toxicity are the objectives of this proposal.